Hypodermic needle for percutaneous drug delivery

ABSTRACT

Devices and methods are disclosed for the percutaneous administration of a composition to a desired in vivo location. The composition comprises a biologically active substance and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier is preferably non-solid and a polymer, which is preferably capable of being transformed into a gel, thus allowing timed-released delivery of the substance. A preferred use for this invention is to provide local delivery of biologically active substances for the prevention of restenosis following angioplasty or other blood vessel injury.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional application of U.S. patent applicationSer. No. 08/816,670, filed on Mar. 13, 1997, now issued as U.S. Pat. No.5,893,839.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to methods and devices foradministering biologically-active substances for delivery to desired invivo locations, as might be particularly useful in treating bloodvessels or grafts following angioplasty procedures.

While systemic administration of drugs or other biologically-activesubstances is satisfactory for many medical treatments, many othertreatments can be facilitated and/or improved with local drug deliveryor administration to selected portions of internal body tissues.Localized drug administration is particularly advantageous where drugretention in the treated locus is required for an effective period oftime without appreciably affecting other body tissues. Strictly by wayof example, drug delivery to a specific locus can be desired in thetreatment of cancerous tumors or the like. In the treatment of suchtumors, often an objective is to administer the cancer drug so that itlocalizes, as much as possible, in the tumor itself in order to limitsystemic toxicity.

Another exemplary treatment for which localized drug delivery isdesirous involves prevention of vessel renarrowing, or restenosis,following percutaneous revascularization techniques, such aspercutaneous transluminal angioplasty (PTA). Although PTA provides analternative to bypass surgery for relieving stenosis of obstructiveatherosclerotic blood vessels, the long-term success of the angioplastyis often compromised by the onset of restenosis thereby requiringreintervention. In the PTA procedure, an inflatable balloon disposed atthe distal end of a catheter is positioned in the region of a stenosis.The balloon is inflated under fluid pressure to reconfigure the narrowedlumen and thereafter permit increased blood flow through the affectedartery. It is not unusual that inflation-deflation cycles will berepeated several times where the narrowing is severe. This mechanicalviolence to the arterial wall may produce the desired opening of theartery, but in delayed consequence the procedure is followed by anestimated 25%-50% incidence of restenosis, typically within 6 months to2 years of the procedure (depending on the location), at or near theinjured site.

Studies have suggested a number of conditions which lead to vesselrestenosis, including remodeling and intimal hyperplasia. These studieshave indicated that vessel injury, such as endothelial denudation,injury to the vascular wall, and rupture of the vasa vasorum, can resultas an unwanted consequence to an angioplasty thereby making the treatedsite susceptible to restenosis. Upon injury, the ensuing deposition ofplatelets, in connection with the vessel's healing mechanism, signalssmooth muscle cell proliferation within the arterial wall. Thedeposition of platelets may lead to acute thrombosis in somecircumstances. More significantly, the proliferation of smooth musclecells is a process which frequently continues unabated and has thereforebeen widely implicated as a prominent factor in the resultingrestenosis. No pharmacologic or mechanical intervention has heretoforeproven sufficiently effective in preventing restenosis followingangioplasties.

2. Description of the Prior Art

The prior art has proposed various techniques that attempt to preventrestenosis following an angioplasty. A mechanical strategy has involvedthe use of stents with the hope that the radial expansile force thatstents exert would restore luminal integrity and preserve maximum vesseldiameter. In use, however, whereas stents have demonstrated some measureof success in limiting abrupt reclosure and remodeling followingvascular intervention, stents have been quite unsuccessful in preventingthe more progressive condition of restenosis. Because of their rigidnature, stents actually can induce vessel injury and hence intrastentthrombosis and restenosis.

Other approaches have focused on the administration of smooth musclecell growth regulators. Most of these approaches have attempted toprovide localized delivery inasmuch as systemic dosing throughintravenous infusion or oral ingestion is inadequate because of the riskof hemorrhage and other complications. For example, Rogers et al.,Circulation, 88:1215-1221 (1993), discuss the use of heparin, aninhibitor of vascular smooth muscle cell proliferation, as a way tolimit neointimal hyperplasia following arterial injury. The Rogers etal. article emphasizes that more chronic and severe vessel damagedemands prolonged administration of antiproliferative agents in order toattenuate the possibility of hyperplasia and restenosis. In practice,however, previous attempts to deliver antiproliferative agents have notmet with success in achieving prolonged prevention of restenosis, asdiscussed in detail below.

Among prior art delivery approaches is the use of catheter systems totreat the primarily local vascular response to injury. In one cathetersystem, an inner balloon is inflated to firmly place an outer balloon ofthe catheter in direct contact with the vessel wall. The outer balloonof the catheter, which is in contact with the vessel, is defined by adrug transport wall which is constructed of a material that isselectively permeable and, thus, permits selective transport of a drugtherethrough. For example, this drug transport wall is constructed ofperforated, permeable, microporous or semipermeable material throughwhich the drug is intended to selectively pass. Another similar cathetersystem contains two separated expansile portions which, whenpressurized, form a space therebetween. Blood may then be removed fromthe space and a biologically active substance may be placed therein tocome into direct contact with the vessel wall. Another catheter systemfor drug delivery is described in U.S. Pat. No. 5,171,217 to March etal. According to March et al., a drug carried by microparticles of aphysiologically-compatible, biodegradable polymer, is intramurallyinjected under directed pressure into the wall of a body vessel in theregion of the affected site.

These catheter delivery systems are unsatisfactory because, among otherthings, the catheter must reside within the blood vessel for asignificant length of time, causing discomfort and inconvenience to thepatient. Further, prolonged instrumentation, as is necessitated by manyintraluminal devices, also increases the risk of thrombosis.Additionally, even after a significant length of time, insufficientamounts of the drug typically enter the target cells to achieve thedesired result. Indeed, a significant problem with delivery of drugs viacatheter systems is that the drug is diluted and carried away in theturbulent and high velocity blood stream. Accordingly, high pressuretransmural perfusions from intravascular catheters merely providetransient luminal drug delivery inasmuch as lasting drug levels in thevessel have not been demonstrated. Significantly, the perfusion catheteritself produces local injury and necrosis to the endothelium andadjacent tissue, presumably as a result of the high pressures used toinstill drugs, and, as such, actually induces restenosis whiledelivering a drug for the purpose of preventing restenosis. Theseprocedures also add to the time, cost, complexity, pain and morbidityof, for example, post-angioplasty procedures and do not result inadequate dosage of the active substance to target cells. There is also asignificant risk that systemic levels of drug will be achieved whenperfusion catheters are utilized for drug delivery.

Other approaches for drug delivery have attempted to combine themechanical support offered by stents with drug delivery. For example,Rogers and Edelman, Journal of Interventional Cardiology, 5:195-201(1992), describe the use of endovascular stents containing drug-elutingcoatings. This drug delivery system was devised to overcome intrastentthrombosis, a condition which plagued previous stent placementprocedures. However, drug-eluting coatings do not permit a sustainedreduction in smooth muscle cell proliferation. In this regard, thesecoated stents release most of their drug within the first hours ofdeployment and do not provide penetrating delivery to the vessel wallfor a prolonged period of time. Another approach is found in Slepian,Contemporary Interventional Techniques, 12:715-737 (1994), whichdescribes time-limited endoluminal wall support in the form of polymericendoluminal paving. In this system, tubes or sheets of biodegradabledrug delivery polymers are transported intraluminally via a cathetersystem and locally thermoformed, yielding supportive, thin polymericendoluminal liner layers. This type of drug delivery is alsounsatisfactory because it requires placement using a catheter, does notyield prolonged drug delivery, and is associated with a significantincrease in the time, cost, complexity, pain and morbidity of relatedprocedures.

Similarly, Hill-West et al., Proc. Natl. Acad. Sci., 91:5967-5971(1994), describe the application of hydrogel barriers that are providedon the inner surface of injured arteries. According to Hill-West et al.,the barrier can be used for the controlled release of macromoleculardrugs. As the gel loosens by degradation, the drug is slowly released.This approach likewise suffers from an inadequate residence time becausemuch of the drug that is delivered dissolves downstream away from thedesired localized site. The proposal identified by Hill-West et al. isalso greatly restrained inasmuch as drug delivery is not possible afterthe gel dries.

Yet another type of localized drug delivery is described in Edelman etal., Proc. Natl. Acad. Sci., 87:3773-3777 (1990). Edelman et al. discusssite-specific therapy following vascular interventions in whichethylene/vinyl acetate copolymer matrix is utilized to permit heparindelivery over time. In practice, however, the approach described byEdelman et al. is ill-suited for treating restenosis in vivo because thematrices must be surgically deployed. Because angioplasties and otherintravascular interventions demonstrate value by producing desiredresults while obviating the need for open operation, the performance ofan operation to improve the results of an intravascular interventionnegates the clinical value of that interventional procedure.

Despite the availability of the foregoing prior art approaches, it willbe appreciated that there still exists a need in the art for a method oflocalized drug delivery which does not require a surgical procedure andwhich delivers a drug in a timed-release fashion wherein the drugdelivery is sustained in its desired localized site. For example, thereexists a specific need for localized drug delivery to blood vessels orgrafts in order to inhibit the onset of restenosis following angioplastyor other intravascular interventions in which the drug delivery isreleased over time and wherein the drug does not get carried away in theblood stream or get undesirably diluted therein. There also exists aneed for drug delivery to blood vessels or grafts in which a vessel'slumen and endothelium are not subject to injury and in which a surgicalprocedure is not required.

SUMMARY OF THE INVENTION

The aforesaid problems are solved, in accordance with the presentinvention, by methods and devices for percutaneously administeringsustained, timed-release localized drug delivery of biologically activesubstances to desired in vivo locations. One aspect of the presentinvention relates to the methods of drug delivery. Administration ofcompositions described herein is accomplished by delivering to thedesired locus a composition comprising a biologically active substanceand a pharmaceutically acceptable carrier. The pharmaceuticallyacceptable carrier is preferably a polymer, for example, apolysaccharide such as alginate. Although the carrier can be in the formof a solid, preferred carriers are non-solid. More preferably, thenon-solid carrier is compatible with a cross-linker which converts thefirst composition into a less mobile gel or solid.

The methods of the present invention can be utilized with any desired invivo locus, such as a vessel, organ, tissue or cavity that can bepercutaneously treated. The desired locus can be treated under themethods of the present invention by delivering biologically activesubstances into, around, or adjacent to the locus, as desired. By way ofexample, in one embodiment the methods of drug delivery under thepresent invention can be utilized to treat a blood vessel or graft thathas been subject to an endovascular procedure, for example, anangioplasty or stent placement, by providing biologically activesubstances substantially around the vessel or graft without intramurallyentering the interior thereof. Specifically, biologically activesubstances, including, but not limited to, drugs such as heparin(including modified forms of heparin such as NAC-heparin) can beinjected into a periadventitial area of the blood vessel or graft thathas been subject to the angioplasty without traversing the endotheliumand lumen of the vessel. For clarity of description, the term“periadventitial” is meant to include the adventitia of a vessel, aswell as soft tissues near the adventitia. The biologically activesubstances are injected nonintramurally, meaning that the injection doesnot traverse the endothelium and lumen, although the substances maydiffuse to an intramural location subsequent to the injection.Significantly, the methods under the present invention do not createfurther injury to blood vessels, particularly the lumen and endothelium,and therefore do not promote the onset of restenosis. In addition, thenovel percutaneous methods of the present invention do not require asurgical procedure.

Another aspect of the present invention relates to a device foradministering biologically active substances to a desired in vivo locusunintrusively and quickly. The device is of a tubular configuration andis capable of delivering compositions by injection. The tubular memberhas at least one lumen therethrough. Although the tubular member can beof a substantially linear configuration, the tubular member canalternatively comprise a first section which lies along a longitudinalaxis of the member and a second section which lies substantially alongan arc, and terminates in a piercing part having at least one lumenopening for the passage of predetermined selected compositions.

Percutaneous administration of compositions, for example to theperiadventitial surface of a blood vessel or graft, yields severaladvantages. For example, percutaneous administration is simpler andfaster than surgical deployment, requiring only a tubular member andsyringe. The present invention is less painful to the patient, as it canbe done entirely under local anesthesia at the time of the primaryprocedure, whether it involves an angioplasty, atherectomy, the stentingof arteries, veins, bypass grafts or dialysis grafts or otherendovascular procedure, leaving only a puncture site rather than anincision. Further, percutaneous administration under the presentinvention is less likely to result in complications such as woundinfection or injury to surrounding tissues. These compositions wouldalso be amenable to use at the time of surgical creation of bypass ordialysis grafts, applied directly to the adventitial surface of theblood vessel or outside surface of the graft.

The present invention will be more fully understood upon reading thefollowing detailed description of the preferred embodiments inconjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

Although the characteristic features of this invention will beparticularly pointed out in the claims, the invention itself, and themanner in which it may be made and used, may be better understood byreferring to the following descriptions taken in connection with theaccompanying drawings forming a part hereof, wherein reference numeralsrefer to like parts throughout the several views.

FIG. 1 is a side elevation view of an embodiment of a slender, tubulardevice according to the present invention shown in conjunction with asyringe, having a cut-out cross-sectional view depicted therein.

FIGS. 2 and 3 represent side elevation views of alternative embodimentsof tubular devices according to the present invention, having cut-outcross-sectional views depicted therein.

FIG. 4 is a cross-sectional view of a blood vessel or graft and a sideview of an embodiment of a tubular device according to the presentinvention, illustrating a preferred relationship between a blood vesselor graft and an inventive tubular device in exemplary use according toinventive methods and also illustrating various regions in aperiadventitial area of the blood vessel or graft.

FIGS. 5-7 are cross-sectional views of blood vessels or grafts and sideviews of alternative embodiments of inventive tubular devices,preferably used for exemplary applications relating to blood vessels ofdifferent sizes and at different depths beneath the patient's skin.

FIG. 8 is a longitudinal cross-sectional view of a blood vessel or graftand a front view of an embodiment of a tubular device according to thepresent invention.

FIG. 9 represents a side elevation view of an alternative embodiment ofa tubular device comprising a cannula and a trocar in accordance withthe present invention.

FIG. 10A represents a front elevation view of an exemplary embodiment ofa linear tubular member comprising two lumens having a cut-outcross-sectional view therein to show an internal section in accordancewith the present invention.

FIG. 10B represents a side elevation view of an exemplary embodiment ofa curved tubular member broken away to reveal two trocars for use withtwo lumens in accordance with the present invention.

FIG. 11A represents a side elevation view of an alternative embodimentof a tubular member comprising two lumens, broken away to reveal outerand inner lumens in accordance with the present invention.

FIG. 11B represents a cross-sectional view of the tubular memberdepicted in FIG. 11A, taken along the line 11B—11B.

FIG. 12 represents a cross-sectional perspective view of an upper end ofthe embodiment shown in FIG. 10.

FIG. 13 represents a perspective view of a head piece for coupling theembodiment of the tubular member depicted in FIG. 11A to, for example,syringes.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following portion of the specification, taken in conjunction withthe drawings, sets forth the preferred embodiments of the presentinvention. The embodiments of the invention disclosed herein include thebest mode contemplated by the inventor for carrying out the invention ina commercial environment, although it should be understood that variousmodifications can be accomplished within the parameters of the presentinvention.

The present invention relates to percutaneous administration of acomposition comprising a biologically active substance and a carrier,preferably a polymeric carrier, to any desired locus within the body.Although the following discussion relates to administering biologicallyactive substances to blood vessels or grafts, it is understood that thisdiscussion is merely illustrative, and the drug delivery of the presentinvention can be applied to other locations within the body.

Referring now to the drawings, FIG. 1 illustrates an exemplaryembodiment of a slender, tubular member or device 10, in accordance withthe present invention. In general, this embodiment provides a means anda system for delivering a composition comprising a biologically activesubstance and a pharmaceutically acceptable carrier to a specificdesired body locus, such as a blood vessel or graft. This deliverymechanism provides for treatment of a localized area of the locus ortreatment of a localized area of tissue adjacent thereto, with minimal,if any, undesirable effects on other body tissues.

The tubular device 10 of this embodiment comprises a hypodermic needle11 having a lumen 12 therethrough. This embodiment includes a firstsection 13 that is substantially linear and which lies along alongitudinal axis of the hypodermic needle 11, and a second section 14which is fluidly connected to the first section and which curvessubstantially along an arc. The second section 14 terminates in apiercing part 15 which contains a lumen opening 16. One of ordinaryskill in the art will appreciate that a hub 17 can be provided toselectively couple the needle 11 with a syringe 18. Stopping means, forexample in the form of an obturator (not shown), can be provided topreclude release of substances at a premature or otherwise undesiredtime and to prevent plugging of the device 10. Devices 10 according tothe present invention are made using standard manufacturing practicesand are preferably used according to inventive methods described herein.

Alternative embodiments of devices 10 under the present invention aredepicted in FIGS. 2-3 and 9. In FIG. 2, the piercing part 15 of thehypodermic needle 11 is oriented such that the lumen opening 16 facessubstantially toward the interior of a circle or ellipse defined by thearc of the second section 14, termed “curved section” herein.Alternatively, FIG. 3 depicts an embodiment wherein the lumen opening 16faces in a direction not lying within the plane of a circle or ellipsedefined by the arc. It can readily be seen by one of ordinary skill inthe art that the lumen opening 16 could alternatively face away from theinterior of the circle or ellipse in a direction substantially in aplane defined by the circle or ellipse or in any other direction rotatedaround the hypodermic needle 11.

As seen in FIG. 9, a preferred embodiment of the device 10 comprises acannula 20 encasing a trocar 22 which contains the piercing part 15.This telescoping arrangement is advantageous because of the additionalsupport offered by the trocar 22. The trocar 22 can be selectivelyremoved to permit injection of substances as desired. The combination ofthe cannula 20 and trocar 22 shown in FIG. 9 is a preferred alternativeto the unitary hypodermic needle 11 shown in FIGS. 1-3. It is noted thatthe preferred device 10 shown in FIG. 9 can be constructed in variousarrangements with regard to the position of the lumen opening 16,including either embodiment shown in FIGS. 2 and 3.

Referring now to the embodiments depicted in FIGS. 4-7, the curvedsection 14 is configured such that, when inserted into a patient's skin30 directly above a blood vessel or graft 31, it can be advanced arounda first side 33 of the blood vessel or graft 31 to a point substantiallyoverlying the blood vessel or graft 31 opposite the skin 30. As such, itcan be readily seen by one skilled in the art that curved sections 14having various radii and having various arc lengths would be appropriatefor use associated with various blood vessels or grafts having differentdiameters and depths beneath the skin.

The dimensions of the preferred device will vary depending upon the typeof application and its location. For example, brachial arteries anddialysis conduits are often only a few millimeters under the skin inthin people, whereas femoral arteries may be 10 centimeters or moreunder the skin in obese people. Diseased radial, ulnar, tibial orperoneal arteries may be only 1 or 2 millimeters in diameter, whereaslarge femoral arteries or axillary veins may be over 8 millimeters indiameter. It can readily be seen that the curved section 14 of aninventive device 10 to be used to treat radial or dorsalis pedisarteries, which have very small diameters and which are very close tothe skin, would have a relatively small radius and a relatively smallarc length. By way of contrast, a preferred device 10 for use associatedwith the deeper femoral artery, which has a relatively large diameterand is relatively deep beneath the skin, would comprise a curved section14 having a relatively large radius and a relatively large arc length.

It can readily be seen that a tubular device 10 formed according to thepresent invention must have a gauge which offers sufficient rigidity tomaintain the appropriate arc. In addition, it can be readily seen thatthe preferred gauge “g” of the device 10 will be dependent upon theviscosity of the injected composition. As such, a device 10 smaller thanabout 21 g would likely clog too easily, and may fail to retain theappropriate arc in use. A preferred device 10 of the present invention,therefore, has a gauge from about 21 g to about 18 g. More preferably,the tubular device 10 has a gauge from about 20 g to about 19 g.

The inventive device 10 described above is preferably used foradministering a biologically active substance to the specific desiredlocus within the body, such as a periadventitial surface of a bloodvessel or graft 31 in vivo. Preferably, the substance is administered bydelivering to the periadventitial area overlying the blood vessel orgraft 31 in vivo a composition comprising a biologically activesubstance and a pharmaceutically acceptable carrier for releasing thesubstance over a period of time. Most preferably, the composition isdelivered substantially completely around the blood vessel or graft inrelatively close proximity to the adventitial surface of the bloodvessel or graft. Ideally, a ring would be formed substantially aroundthe periadventitial surface; however, it can readily be seen thatplacing the composition reasonably near the periadventitial surface willachieve the desired result of delivering active substances to cells ofthe vessel wall or cells adjacent to a graft.

Referring again to FIGS. 4-7 and FIG. 8, for treatment of a blood vesselor graft 31 according to an exemplary utility for the.present invention,the device 10 is preferably advanced under a patient's skin 30 such thatthe piercing part 15 of the device 10 moves around a first side 33 ofthe blood vessel or graft 31 to a first location 34 in theperiadventitial area of the blood vessel or graft 31. The first location34 is preferably opposite the blood vessel from the skin 30. Next, thecomposition is injected through the lumen opening 16 as the piercingpart of the tubular device 10 is withdrawn from the first location 34 toa second location 35. A second location 35 is preferably between theblood vessel or graft 31 being treated and the patient's skin 30. Next,the device 10 is advanced such that the piercing part 15 moves around asecond side of the blood vessel or graft 31 to a third location 37. Thisthird location 37 is preferably near the first location 34. Next, thecomposition is injected through the lumen opening 16 as the piercingpart 15 is withdrawn from the third location 37 to a fourth location 38which is substantially the same as the second location 35. The devicemay then be withdrawn from the skin 30.

It is noted that the above method may be usefully performed using alinearly straight tubular device in accordance with the presentinvention. In a preferred embodiment, however, an inventive device 10having a curved section 14 is used. A curved device 10 with theappropriate radius, as described hereinabove, can be advanced through asingle puncture site around a blood vessel, closely hugging theperimeter of that vessel. As the device 10 is withdrawn, the polymer canbe administered closely to the outer surface, the adventitia, of thatblood vessel. Without removing the device 10 completely from thepatient, the device 10 can be rotated 180° and advanced around the otherside of the blood vessel, allowing introduction of the polymer on thatside. It would be more difficult to remain close to the adventitia ofthe blood vessel if a straight tubular device were used. In thisembodiment, the most preferred device 10 would be one having a radiusand an arc length capable of delivering the composition closely to thedeepest wall of the vessel or graft 31 from a single percutaneouspuncture.

As mentioned above, the composition being injected preferably comprisesa biologically active substance and a pharmaceutically acceptablecarrier for releasing a substance over a period of time. Thebiologically active substance may include, for example, a gene, a generegulator, an antibody, a polypeptide, a radioactive composition, or adrug. Examples of drugs which are preferably used in accordance with thepresent invention in the context of blood vessels or grafts are heparin,hirudin, an enzyme inhibitor, estrogen, and angiopeptin. These lists,however, are not intended to be exhaustive, and the present inventioncontemplates a wide variety of substances which serve as usefulbiologically active substances depending upon the locus and particulartreatment involved.

Although the pharmaceutically acceptable carrier of the presentinvention may be any of a wide variety of pharmaceutically acceptablecarriers, a preferred carrier is a polymer. In addition, although solidcarriers, including but not limited to microcapsules, that are capableof being injected by a tubular device 10 can be utilized under thepresent invention, the carrier is preferably “non-solid.” As usedherein, the term “non-solid carrier” is intended to refer to a carrierwhich has physical characteristics similar to a liquid or a gel andwhich is capable of being injected through a tubular device 10. In apreferred embodiment, the pharmaceutically acceptable non-solid carrieris a liquid polymer capable of being cross-linked and thus convertedinto a gel or a solid upon being mixed with a suitable cross-linker. Asused herein, the term “cross-linker” is meant to refer to a substancewhich, when mixed with a specific non-solid polymer, will cause thenon-solid polymer to be converted to a gel or solid. In accordance withthis embodiment, the cross-linker is preferably delivered into theperiadventitial area simultaneously with or subsequent to the deliveryof the first composition. Most preferably, the first composition and thecross-linker are delivered by injection through a tubular device 10under the present invention.

In one preferred embodiment, the polymer is a polysaccharide.

More.preferably, the polymer is one capable.of being cross-linked whenmixed with a cross-linker as noted above. One example of a polymercapable of being cross-linked is alginate, and preferred cross-linkersfor use therewith include divalent cations such as calcium, for examplein the form of calcium chloride or calcium gluconate. The desired effectmay be obtained with regard to alginate by using as a cross-linker awide variety of divalent cations. However, various divalent cations havedifferent effects upon the gel, the substance carried therein, and thesurrounding tissue. As such, the preferred divalent cations selected fora particular use will depend on the carrier being used, the substancebeing delivered, and the specific in vivo location of the delivery.

The term “alginate” as used herein is intended to designate a family ofunbranched binary copolymers of 1-4-linked β-D-mannuronic acid (M) andα-L-guluronic acid (G). Alginates have widely varying compositions andsequences, depending on the organism and the tissue from which they areisolated. The monomers are arranged in a pattern of blocks along thechain, with homopolymeric regions (termed M and G blocks) interspersedwith regions of alternating structure (MG blocks). Thus, when inventivemethods are used to deliver a composition comprising a biologicallyactive substance, as most preferably carried in a pharmaceuticallyacceptable non-solid polymer capable of being cross-linked, to a desiredlocation such as the periadventitial area overlying the blood vessel orgraft in vivo, a subsequent injection of a cross-linker causes the firstnon-solid composition to be converted to a gel or a solid, therebyadvantageously becoming more apt to remain immobilized. Accordingly, apreferred method for treating a blood vessel or graft in vivo with thebiologically active substance comprises a non-solid carrier andadditionally comprises injecting a second non-solid composition into thefirst non-solid composition, wherein the second non-solid compositioncomprises a cross-linker, prior to withdrawing the piercing part 15 ofthe tubular device 10 from the skin.

Additionally contemplated by this invention are methods and devices forinjecting the first composition and a cross-linker simultaneously. Asseen in FIGS. 10-13, in a preferred method a tubular device 10 is usedwhich has more than one lumen 12 a and 12 b, and is thus capable ofinjecting the first composition and the cross-linker simultaneously. Forexample, FIGS. 10A and 10B depict a first exemplary arrangement of atubular member 10 which comprises two substantially semicircular (incross-section) lumens 12 a and 12 b disposed side-by-side separated by aseptum 40. Septum 40 isolates the two lumens 12 a and 12 b into separatechambers thereby permitting segregated simultaneous flow of differentcompositions, as desired, without premature mixing thereof. Septum 40can terminate at or near the piercing part 15 so that the firstcomposition and the cross-linker can be mixed after or just before theyexit at least one lumen opening.

FIG. 10A illustrates the side-by-side lumens 12 a and 12 b in a lineartubular member 10, while FIG. 10B shows the side-by-side lumens 12 a and12 b in a curved tubular member 10. As seen in FIG. 10B, a pair oftrocars 22 a and 22 b can be disposed in corresponding lumens ifdesired, although placing a trocar in only one lumen is also possible.The trocars 22 a and 22 b for the side-by-side arrangement arepreferably substantially configured in a D-shape so as to beparticularly compatible with the semicircular lumens 12 a and 12 b. Itwill be appreciated that the two D-shaped trocars 22 a and 22 b can forma conical or pyramidal piercing portion 15, although each trocar can beconfigured to form a conventionally shaped piercing portion, which isparticularly useful if only one trocar is desired.

FIGS. 11A-11B depict an alternative double-lumen arrangement comprisingan outer lumen 12 a and an inner lumen 12 b. For convenience inmanufacture and use, the outer and inner lumens 12 a and 12 b incross-section can preferably be fixed along a line tangent to bothlumens 12 a and 12 b, as best seen in FIG. 11B. However, the inner lumen12 b can alternatively be wholly contained within a perimeter of theouter lumen 12 a if desired. The inner lumen 12 b is more readilyconducive to receiving a trocar, if desired, than the outer lumen 12 a,which can be, for example, moon-shaped. By using a singular trocar withinner lumen 12 b while not utilizing .a trocar with outer lumen 12 a,the structural support provided by the singular trocar can be sufficienteven in a double-lumen arrangement. It is emphasized for clarity ofdescription that the alternative side-by-side and inner/outerdouble-lumen arrangements can be used in both linear and curved tubularmembers in accordance with the present invention. One of ordinary skillin the art will also appreciate that the alternative double-lumenarrangements can also be utilized with unitary tubular memberscomprising, for example, a hypodermic needle, or with cannula/trocararrangements as described hereinabove. Also, the position of the lumenopening can vary as described above in conjunction with FIGS. 2-3.

Referring to FIG. 12, the septum 40 preferably fully extends to a top 41of the hub 17, or axially adjacent thereto, for the side-by-sidearrangement shown in FIGS. 10A and 10B. By extending the septum 40,isolation of the lumens 12 a and 12 b is optimized thereby protectingseparated compositions from premature mixing as desired compositions arereceived by the lumens 12 a and 12 b, for example, through correspondingreceiving portions in the hub 17 or directly. The hub 17 is alsopreferably provided with locking means such as a notch 42 that can fitwith, for example, a predetermined closure, syringe or other objecthaving, for example, a protrusion which aligns with or otherwise matchesthe notch 42. The locking means prevents an opportunity for an undesiredsyringe or cap to engage with an unintended lumen in the tubular member.

As seen in FIG. 13, a preferred hub 17 for use with the outer/innerlumens 12 a and 12 b shown in FIGS. 11A and 11B comprises a head portion44 including receiving portions 46 a and 46 b which are adapted toreceive a syringe, another source for desired compositions, or aclosure. The receiving portion 46 b that corresponds to the inner lumen12 b vertically extends from head 44 and, as noted above, canselectively retain a trocar if desired. The receiving portion 46 a thatcorresponds to the outer lumen 12 a extends horizontally or laterallyfrom head 44 and is therefore substantially perpendicular relative toreceiving portion 46 b. It will be appreciated that placement of atrocar is inconvenient in receiving portion 46 a, and hence outer lumen12 a, because of this lateral placement.

As an illustration of a specific use of the inventive devices andmethods, after a patient undergoes an angioplasty, stenting or otherendovascular procedure of an artery, vein, or a graft, the patient'sskin overlying that vessel will be sterilely prepped and draped if it isnot already within the sterile field while the patient remains in theprocedural suite. An inventive curved tubular member or device 10 isadvanced through the skin overlying the vessel at the selected site,around the vessel to the portion of the vessel furthest from the skin.In accordance with the preferred constructed embodiment of the presentinvention, the inner trocar 22 of the device 10 is removed, and thefirst composition is injected as the trocar 22 is withdrawn. The device10 is withdrawn to a location adjacent the skin, but not completely outof the patient. The device 10 is turned 180°, advanced around the otherside of the vessel, and the first composition is introduced on this sideof the vessel as well. A cross-linker is injected into the firstcomposition, if needed, and the device 10 is completely removed from thepatient. The patient can then be immediately discharged from theprocedural suite with very little time having been spent undergoingtime-consuming procedures and observation previously associated with thethreat of restenosis. The polymer allows timed-release of the drug withpredetermined optimal release kinetics. Since the administered drugwould be in the soft tissues immediately surrounding the vessel, such asthe adventitia, as opposed to the lumen and endothelium, the drug wouldnot be washed quickly away, in contradistinction to the currentlyavailable intraluminal methods of drug administration.

While the preferred embodiments of the invention have been disclosed, itshould be appreciated that the invention is susceptible to modificationwithout departing from the spirit of the invention or the scope of thesubjoined claims. As noted above, the present invention can be directedto any locus in the body, and is not limited to application to bloodvessels and grafts. For example, the present invention can be used topercutaneously administer a biologically active substance and a carrier,preferably a non-solid carrier that is compatible with a crosslinker,into, around and/or adjacent to the desired locus, as desired, asperhaps to provide localized drug delivery to a tumor located within anorgan.

What is claimed is:
 1. A hypodermic needle for percutaneously deliveringdesired biologically active substances, the needle comprising a tubularmember having a selected radius, the tubular member comprising: (a) atleast two lumens therethrough, (b) a first section which lies along alongitudinal axis of the tubular member, and (c) a second sectionfluidly connected to the first section; the second section lyingsubstantially along an arc and terminating in a piercing part locatedoff of the longitudinal axis which includes at least one lumen openingtherein.
 2. A hypodermic needle as defined in claim 1, wherein thetubular member has a gauge of from about 21 gauge to about 18 gauge. 3.A hypodermic needle as defined in claim 1, wherein the tubular memberhas a gauge of from about 20 gauge to about 19 gauge.
 4. A hypodermicneedle as defined in claim 1, wherein the piercing part is located offsaid longitudinal axis by a distance which is at least two times saidradius.
 5. A hypodermic needle as defined in claim 1, wherein thepiercing part is located off the longitudinal axis by a distance whichis at least several times said radius.
 6. A hypodermic needle forpercutaneously delivering at least two compositions simultaneously, theneedle including a tubular member comprising: (a) a first lumen capableof delivering a first composition; (b) a second lumen capable ofdelivering a second composition; (c) at least one lumen opening fluidlyconnected to the first and second lumens for outputting the compositionsfrom the device; (d) a piercing part; and (e) a hub that includes (i) afirst receiving portion that selectively permits inputting the firstcomposition into the first lumen, (ii) a second receiving portion forselectively inputting the second composition into the second lumen, and(iii) a head portion, wherein the first receivingportion extendssubstantially vertically from the head portion and wherein the secondreceiving portion extends substantially horizontally from the headportion.
 7. A hypodermic needle as defined in claim 6 wherein the firstreceiving portion is adapted to receive a trocar.
 8. A hypodermic needlefor percutaneously delivering desired biologically active substances,the needle including a tubular member comprising: (a) an outer walldefining an internal cavity; and (b) a partition dividing the internalcavity of said tubular member into two separate lumens, wherein thetubular member includes a first section which lies along a longitudinalaxis of the tubular member, and a second section fluidly connected tothe first section, and wherein the second section lies substantiallyalong an arc and terminates in a piercing part located off of thelongitudinal axis which includes at least one lumen opening therein.